The dystrophin-glycoprotein complex (DGC) in skeletal muscle is a complex of sarcolemmal proteins and glycoproteins. It is composed of dystrophin, a cytoskeletal actin-binding protein; the syntrophins, a 59 kDa triplet of intracellular proteins that bind the C-terminal domain of dystrophin; .alpha.-dystroglycan, a 156 kDa extracellular proteoglycan which binds the G domain of laminin; .beta.-dystroglycan, a 43 kDa transmembrane glycoprotein which binds the cysteine-rich region of dystrophin, .alpha.-, .beta.-, and .gamma.-sarcoglycan, transmembrane glycoproteins of 50, 43, and 35 kDa respectively; and a 25 kDa transmembrane protein. Recent experiments have demonstrated the existence of two complexes within the DGC: the dystroglycan complex, composed of .alpha.- and .beta.-dystroglycan, and the sarcoglycan complex, consisting of .alpha.-, .beta.-, and .gamma.-sarcoglycan.
Defects in DGC components lead to muscle fiber necrosis, the major pathological event in muscular dystrophies. In Duchenne muscular dystrophy (DMD), mutations in the dystrophin gene cause the loss of dystrophin and a reduction of the dystrophin-associated proteins. One form of congenital muscular dystrophy (CMD) has recently been characterized as being caused by mutations in the laminin .alpha.2-chain gene. Limb-girdle muscular dystrophy (LGMD) represents a clinically and genetically heterogeneous class of disorders. They are inherited as either autosomal dominant or recessive traits. An autosomal dominant form, LGMD1A, was mapped to 5q31-q33 (Speer, M. C. et al., Am. J. Hum. Genet. 50:1211, 1992; Yamaoka, L. Y. et al., Neuromusc. Disord. 4:471, 1994), while six genes involved in the autosomal recessive forms were mapped to 15q15.1 (LGMD2A)(Beckmann, J. S. et al., C. R. Acad. Sci. Paris 312:141, 1991), 2p16-pl3 (LGMD2B)(Bashir, R. et al., Hum. Mol. Genet. 3:455, 1994), 13q12 (LGMD2C) (Ben Othmane, K. et al., Nature Genet. 2:315, 1992; Azibi, K. et al., Hum. Mol. Genet. 2:1423, 1993), 17q12-q21.33 (LGMD2D)(Roberds, S. L. et al., Cell 78:625, 1994; McNally, E. M., et. al., Proc. Nat. Acad. Sci. U.S.A. 91:9690, 1994), 4q12 (LG1MD2E) (Lim, L. E., et. al., Nat. Genet. 11:257, 1994; Bonnemann, C. G. et al. Nat. Genet. 11:266, 1995), and most recently to 5q33-q34 (LGMD2F)(Passos-Bueno, M. R., et. al., Hum. Mol. Genet. 5:815, 1996). Patients with LGMD2C, 2D and 2E have a deficiency of components of the sarcoglycan complex resulting from mutations in the genes encoding .gamma.-, .alpha.-, and .beta.-sarcoglycan respectively. The gene responsible for LGMD2A has been identified as the muscle-specific calpain, whereas the genes responsible for LGMD1A, 2B and 2F are still unknown.